Ludwig Stanford’s Tushar Desai and colleagues identified in mouse models a new cell of origin for lung adenocarcinoma: the AT1 cell, which was not thought to be able to initiate lung cancers because it is not a stem cell. The AT1 cell, they showed, generates tumors that resemble lepidic cancer, a slow-growing malignancy that spreads along alveolar walls. Tushar’s lab has previously shown that aggressive lung adenocarcinomas are initiated by transformed AT2 cells, which are stem cells. He and his colleagues found that oncogenic KRASG12D—which is known to drive aggressive lung cancers, among other malignancies—reprograms AT1 cells into their parent AT2 stem cells. It is these reprogrammed cells that then go on to seed cancer. The tumors they form grow slowly, however, unlike the aggressive adenocarcinomas generated by AT2 cells. The latter are often driven by the signaling protein WNT. But in AT1-derived cancer, Tushar and his colleagues found, WNT activation has antitumor effects. This has significant implications for the personalization of lung cancer therapy, since the WNT pathway is considered a prime target for cancer therapies. In AT-1 derived cancers, however, its blockade might prove counterproductive.
KRAS(G12D) drives lepidic adenocarcinoma through stem-cell reprogramming
Nature, 2023 July 19